Alzheimer's disease (AD) is the most common form of dementia and an important cause of morbidity and mortality in the U.S. AD and the complications of atherosclerotic cardiovascular disease (ASCVD) are strongly associated suggesting common, but unknown, pathogenetic factors. Our proposal will focus on the investigation of the interactions of very low-density lipoprotein (VLDL) lipolysis products with apolipoprotein (apo) E3 and apoE4, brain microvascular endothelial cells and astrocytes, and blood-brain barrier (BBB) permeability. Brain microvascular endothelial cells and astrocytes are important components of the brain neurovascular unit, which governs BBB permeability, and play key roles in the neuropathology of AD. The overall goal of this proposal is to understand the mechanisms of the microvascular contribution to the pathogenesis of AD. This project is an integrated, translational research project that will: (1) Investigate the effects of very low-density lipoprotein (VLDL) lipolysis products on apoE4 conformation and brain microvascular injury and BBB permeability, (2) Examine intracellular signaling pathways by which VLDL lipolysis products injure human microvascular endothelial cells and increase BBB permeability, and (3) Determine the mechanisms by which VLDL lipolysis products injure astrocytes and induce apoptosis. We expect that injury of the neurovascular unit by apoE4 and VLDL lipolysis products could initiate and/or perpetuate AD. We are well positioned to perform these studies because we have an established interdisciplinary research group to complete the aims of the proposal. These proposed studies are innovative and will advance the field by: (1) Providing a better understanding of the vascular determinates of AD, (2) Using an integrated, translational approach to comprehensively investigate a relevant and important clinical problem, Alzheimer's disease, (3) Using new and more sensitive biophysical approaches to examine mechanisms of disease development, (4) Using brain microvascular endothelial cells and astrocytes from AD volunteers, providing more relevant results, (5) Developing a comprehensive new method to measure rodent BBB permeability, and (6) Providing rationales for future therapies for Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an increasingly important cause of morbidity and mortality in the U.S. Recent work has indicated that there is a strong component of microvascular pathology that contributes to Alzheimer's disease. The overall goal of this proposal is to define mechanisms contributing to the development of Alzheimer's disease and design potential therapies to prevent the onset of this devastating condition.